Heterocycle compounds and uses thereof

ABSTRACT

The invention relates to chemical compounds, or pharmaceutically acceptable salts thereof of the formula (Q) or (I), which penetrate the blood-brain barrier, inhibit the formation and accumulation of beta-amyloid, and are useful in the treatment of neurodegenerative diseases, particularly Alzheimer&#39;s disease. Further, the compounds of the present invention inhibit certain kinases, thereby being useful for the treatment of cancers of the central nervous system.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a US filing under 35 USC 371 of InternationalApplication No. PCT/US2008/007167 filed on Jun. 6, 2008, which claimsthe benefit of U.S. Provisional Application 60/933,732 filed on Jun. 7,2007 the contents of each of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel heterocycles, theirpharmaceutical compositions and methods of use. In addition, the presentinvention relates to therapeutic methods that penetrate the blood-brainbarrier and inhibit the formation and accumulation of beta-amyloid.Accordingly, the compounds and compositions of the present invention areuseful in the treatment of neurodegenerative diseases, particularlyAlzheimer's disease. Further, the compounds of the present inventioninhibit certain kinases, thereby being useful for the treatment ofcancers of the central nervous system.

BACKGROUND OF THE INVENTION

Without being bound to theory, it is believed that the pathology ofAlzheimer's disease (“AD”) involves amyloid-β (“Aβ”) peptides, which aremetabolites of β-amyloid precursor protein (Alzheimer'sdisease-associated precursor protein or “APP”), and are believed to bemajor pathological determinants of AD. These peptides consist mainly of40 to 42 amino acids, Aβ1-40 (“Aβ40”) and Aβ1-42 (“Aβ42”), respectively.Aβ40 and Aβ42 are generated by two enzymatic cleavages occurring closeto the C-terminus of APP. The enzymes responsible for the cleavage,β-secretase and γ-secretase, generate the N- and C-termini of Aβ,respectively. The amino terminus of Aβ is formed by β-secretase cleavagebetween methionine residue 596 and aspartate residue 597 of APP(numbering based o APP 695 isoform). γ-secretase cleaves at varyingpositions 38-, 40- or 43-residues C-terminal of this β-secretasecleavage product to release the Aβ peptides. A third enzyme,α-secretase, cleaves the precursor protein between the Aβ- andγ-cleavage sites, thus precluding Aβ production and releasing anapproximately 3 kDa peptide known as P3, which is non-pathological. Bothβ- and α-secretase cleavage also result in soluble, secreted-terminalfragments of APP, known as sAPPβ and sAPPα, respectively. The sAPPαfragment has been suggested to be neuroprotective. These secretases mayalso be involved in the processing of other important proteins. Forexample, γ-secretase also cleaves Notch-1 protein.

A drug which selectively inhibits Aβ formation and/or accumulation isthus of potential interest for the treatment, management and preventionof Alzheimer's disease. To maximize utility, however, it is alsodesirable that it can be readily delivered to relevant site of action inthe brain. Brain is protected from chemical insult by a selectivebarrier, referred to as the blood-brain barrier (“BBB”), that manydrug-like compounds are unable to penetrate.

International Patent Publication No. WO 03/057165 discloses that certainpreviously known inhibitors of tyrosine kinases are useful to inhibitthe production of and accumulation of Aβ. Such compounds included thosedescribed in U.S. Pat. No. 5,521,184, which includes imatinib. Netzer etal., Proc Natl Acad Sci., 100(21):12444-9 (2003) showed that imatinibinhibits production of Aβ without affecting γ-secretase cleavage ofNotch-1 and without unacceptable toxicity to the neurons. A majordisadvantage with using imatinib for the treatment or prevention ofAlzheimer's disease, however, is that penetration of this compoundacross the BBB is poor because imatinib is actively pumped out of thebrain by a P-glycoprotein system, thereby preventing high concentrationsof the compound from accumulating in the brain. Accordingly, imatinib isgenerally not used for the treatment of cancers of the central nervoussystem.

International Patent Publication No. WO 05/072826 describes compositionsand methods of use for tyrosine kinase inhibitors to treat pathogenicinfection. J. Zimmermann et al., Bioorganic & Medicinal Chem. Lett.,7(2):187-192 describes potent and selective inhibitors of theABL-kinase: phenylamino-pyrimidine (PAP) derivatives. InternationalPatent Publication No. EP 1 533 304 describes amide derivatives.International Patent Publication No. WO 04/005281 describes inhibitorsof tyrosine kinases. International Patent Publication No. WO 05/039586describes the use of pyridinyl-pyrimidinylamino-benzamide derivativesfor the treatment of amyloid related disorders. U.S. Pat. No. 5,521,184describes pyrimidine derivatives and processes for the preparationthereof. International Patent Publication No. WO 04/110452 describessubstituted phenyl compounds.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (Q):

in free or salt form, which penetrate the blood-brain barrier, inhibitthe formation and accumulation of beta-amyloid, and are useful in thetreatment of neurodegenerative diseases, particularly Alzheimer'sdisease. Further, the compounds of the present invention inhibit certainkinases, thereby being useful for the treatment of cancers of thecentral nervous system.

The present invention is also directed to compounds of formula (I):

which penetrate the blood-brain barrier, inhibit the formation andaccumulation of beta-amyloid, and are useful in the treatment ofneurodegenerative diseases, particularly Alzheimer's disease. Further,the compounds of the present invention inhibit certain kinases, therebybeing useful for the treatment of cancers of the central nervous system.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the compounds of the present invention are presented by

in free or salt form, wherein:

A¹ is —C(R⁷)— or —N—;

A² and A³ are independently —C— or —N—, wherein at least one of A² andA³ must be N; and wherein when A² is —C—, it optionally is substitutedwith R⁸;

W is —O— or —N(C₀₋₆alkyl)-;

Y is —NHCO—, —CONH—, —NHSO₂—, —NHCONH—, or —NHCH₂—;

D is a 5 or 6 membered aryl, hetaryl or hetcyclic ring having at leastone N, S, or O ring atom, or a C ring atom forming an oxo (C═O) moiety;

R¹ is C₁₋₆alkyl, aryl, or hetaryl; optionally substituted except at theortho position of the aryl or hetaryl with 1-6 halo, C₁₋₆alkoxy,C₁₋₆alkyl, or trifluoromethyl substituents; wherein the ortho aryl orhetaryl position is unsubstituted;

R² is C₀₋₆alkyl, C₃₋₇cycloalkyl, aryl, hetaryl, aryl(C₁₋₄alkyl)-,hetcyclyl(C₀₋₄alkyl)-, or —C₀₋₆alkyl-N(C₀₋₆alkyl)(C₀₋₆alkyl), optionallysubstituted with C₁₋₆alkyl; and

R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are independently selected from hydrogen,halo, C₁₋₄alkyl (e.g., methyl), C₁₋₄alkoxyl (e.g., methoxy), and haloC₁₋₄alkyl (e.g., trifluoromethyl).

In another aspect, the compounds of the present invention arerepresented by formula (I):

in free or salt form, wherein:

A¹ is CH or N;

A² and A³ are independently CH or N, wherein at least one of A² and A³must be N; and wherein when A² is C, it optionally is substituted withhalo, methyl, methoxy, or trifluoromethyl;

W is —O— or —N(C₀₋₆alkyl)-;

Y is —NHCO—, —CONH—, —NHSO₂—, —NHCONH—, or —NHCH₂—;

D is a 5 or 6 membered aryl, hetaryl or hetcyclic ring having at leastone N, S, or O ring atom, or a C ring atom forming an oxo (C═O) moiety;

R¹ is C₁₋₆alkyl, aryl, or hetaryl; optionally substituted except at theortho position of the aryl or hetaryl with 1-6 halo, C₁₋₆alkoxy,C₁₋₆alkyl, or trifluoromethyl substituents; wherein the ortho aryl orhetaryl position is unsubstituted; and

R² is C₀₋₆alkyl, C₃₋₇cycloalkyl, aryl, hetaryl, aryl(C₁₋₄alkyl)-,hetcyclyl(C₀₋₄alkyl)-, or —C₀₋₆alkyl-N(C₀₋₆alkyl)(C₀₋₆alkyl), optionallysubstituted with C₁₋₆alkyl.

In one aspect, the compounds of the present invention are represented byFormula I in free or salt form, wherein W is —O— and the other variablesare as defined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is —O—; Yis —NHCO—; and the other variables are as defined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is —O—; Yis —NHCO—; A² is N; A³ is CH optionally substituted with halo, methyl,methoxy, or trifluoromethyl; and the other variables are as definedabove for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is —O—; Yis —NHCO—; A¹ is CH; A² is N; A³ is CH optionally substituted with halo,methyl, methoxy, or trifluoromethyl; and the other variables are asdefined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is —O—; Yis —NHCO—; A¹ is N; A² is N; A³ is CH optionally substituted with halo,methyl, methoxy, or trifluoromethyl; and the other variables are asdefined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is —O—; Yis —NHCO—; A³ is N; A² is CH optionally substituted with halo, methyl,methoxy, or trifluoromethyl; and the other variables are as definedabove for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is —O—; Yis —NHCO—; A¹ is CH; A³ is N; A² is CH optionally substituted with halo,methyl, methoxy, or trifluoromethyl; and the other variables are asdefined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is —O—; Yis —NHCO—; A¹ is N; A³ is N; A² is CH optionally substituted with halo,methyl, methoxy, or trifluoromethyl; and the other variables are asdefined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —CONH—; and the other variables are as defined above forFormula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —CONH—; A² is N; A³ is CH optionally substituted with halo,methyl, methoxy, or trifluoromethyl; and the other variables are asdefined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —CONH—; A¹ is CH; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —CONH—; A¹ is N; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —CONH—; A³ is N; A² is CH optionally substituted with halo,methyl, methoxy, or trifluoromethyl; and the other variables are asdefined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —CONH—; A¹ is CH; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —CONH—; A¹ is N; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHSO₂—; and the other variables are as defined above forFormula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHSO₂—; A² is N; A³ is CH optionally substituted withhalo, methyl, methoxy, or trifluoromethyl; and the other variables areas defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHSO₂—; A¹ is CH; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHSO₂—; A¹ is N; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHSO₂—; A³ is N; A² is CH optionally substituted withhalo, methyl, methoxy, or trifluoromethyl; and the other variables areas defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHSO₂—; A¹ is CH; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHSO₂—; A¹ is N; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCONH—; and the other variables are as defined above forFormula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCONH—; A² is N; A³ is CH optionally substituted withhalo, methyl, methoxy, or trifluoromethyl; and the other variables areas defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCONH—; A² is N; A¹ is CH; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCONH—; A² is N; A¹ is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCONH—; A³ is N; A² is CH optionally substituted withhalo, methyl, methoxy, or trifluoromethyl; and the other variables areas defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCONH—; A¹ is CH; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCONH—; A¹ is N; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCH₂—; and the other variables are as defined above forFormula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCH₂—; A² is N; A³ is CH optionally substituted withhalo, methyl, methoxy, or trifluoromethyl; and the other variables areas defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCH₂—; A¹ is CH; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCH₂—; A¹ is N; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCH₂—; A³ is N; A² is CH optionally substituted withhalo, methyl, methoxy, or trifluoromethyl; and the other variables areas defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCH₂—; A¹ is CH; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —O—; Y is —NHCH₂—; A¹ is N; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In another aspect, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)- and the other variables are as defined above for FormulaI.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCO—; and the other variables are as definedabove for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCO—; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCO—; A¹ is CH; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCO—; A¹ is N; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCO—; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCO—; A¹ is CH; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In an embodiment of this aspect, the compounds of the present inventionare represented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCO—; A¹ is N; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —CONH—; and the other variables are as definedabove for Formula I.

In yet another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —CONH—; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In yet another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —CONH—; A¹ is CH; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —CONH—; A¹ is N; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —CONH—; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In yet another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —CONH—; A¹ is CH; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —CONH—; A¹ is N; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHSO₂—; and the other variables are as definedabove for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHSO₂—; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHSO₂—; A¹ is CH; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHSO₂—; A¹ is N; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHSO₂—; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHSO₂—; A¹ is CH; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In still another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHSO₂—; A¹ is N; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCONH—; and the other variables are as definedabove for Formula I.

In another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCONH—; A² is N; A³ is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCONH—; A¹ is CH; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCONH—; A¹ is N; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCONH—; A³ is N; A² is CH optionally substitutedwith halo, methyl, methoxy, or trifluoromethyl; and the other variablesare as defined above for Formula I.

In another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCONH—; A¹ is CH; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In another embodiment, the compounds of the present invention arerepresented by Formula I in free or salt form, wherein W is—N(C₀₋₆alkyl)-; Y is —NHCONH—; A¹ is N; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHCH₂—; and the other variables are as definedabove for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHCH₂—; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHCH₂—; A¹ is CH; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHCH₂—; A¹ is N; A² is N; A³ is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHCH₂—; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHCH₂—; A¹ is CH; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In yet another embodiment of this aspect, the compounds of the presentinvention are represented by Formula I in free or salt form, wherein Wis —N(C₀₋₆alkyl)-; Y is —NHCH₂—; A¹ is N; A³ is N; A² is CH optionallysubstituted with halo, methyl, methoxy, or trifluoromethyl; and theother variables are as defined above for Formula I.

In another aspect, the present invention comprises any of the followingcompounds:

The invention therefore comprises any of the following:

-   -   1.1 Compounds of Formula (Q) or Formula (I), wherein W is —O— or        —N(C₀₋₆alkyl)-;    -   1.2 Compounds of Formula (Q) or Formula (I) or 1.1, wherein W is        —N(C₀₋₆alkyl)-;    -   1.3 Compounds of Formula (Q) or Formula (I) or 1.1 or 1.2,        wherein W is —NH—;    -   1.4 Compounds of Formula (Q) or Formula (I), 1.1-1.3, wherein Y        is —NHCO—, —CONH—, —NHSO₂—, —NHCONH—, or —NHCH₂—;    -   1.5 Compounds of Formula (Q) or Formula (I), or any of 1.1-1.4,        wherein Y is —NHSO₂—;    -   1.6 Compounds of Formula (Q) or Formula (I), or any of 1.1-1.4,        wherein Y is —CONH—;    -   1.7 Compounds of Formula (Q) or Formula (I), or any of 1.1-1.4,        wherein Y is —NHCO—;    -   1.8 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.7,        wherein A¹ is —N—;    -   1.9 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.7,        wherein A¹ is —C(R⁷)—;    -   1.10 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.7        or 1.9, wherein A¹ is —C(H)—;    -   1.11 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.10,        wherein A² is —N—;    -   1.12 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.10,        wherein A² is —C— optionally is substituted with R⁸;    -   1.13 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.12,        wherein A³ is —N—;    -   1.14 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.11,        wherein A³ is —C— optionally is substituted with R⁸;    -   1.15 Formula 1.14, wherein R⁸ is hydrogen, halo, C₁₋₄alkyl        (e.g., methyl), C₁₋₄alkoxyl (e.g., methoxy), or haloC₁₋₄alkyl        (e.g., trifluoromethyl);    -   1.16 Formula 1.14 or 1.15, wherein R⁸ is hydrogen    -   1.17 Formula 1.14, wherein R⁸ is C₁₋₄alkyl (e.g., methyl);    -   1.18 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.17,        wherein D is a 5 or 6 membered aryl, hetaryl or hetcyclic ring        having at least one N, S, or O ring atom or a C ring atom        forming an oxo (C═O) moiety;    -   1.19 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.18,        wherein D is a 5 or 6 membered aryl, hetaryl or hetcyclic ring        having at least one N, S, or O ring atom;    -   1.20 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.19,        wherein D is aryl;    -   1.21 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.20,        wherein D is phenyl;    -   1.22 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.21,        wherein R¹ is C₁₋₆alkyl, aryl, or hetaryl; optionally        substituted except at the ortho position of the aryl or hetaryl        with 1-6 halo, C₁₋₆alkoxy, C₁₋₆alkyl, or trifluoromethyl        substituents;    -   1.23 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.22,        wherein R¹ is aryl optionally substituted except at the ortho        position of the aryl with 1-6 halo, C₁₋₆alkoxy, C₁₋₆alkyl, or        trifluoromethyl substituents;    -   1.24 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.23,        wherein R¹ is phenyl optionally substituted except at the ortho        position of the phenyl with 1-6 halo, C₁₋₆alkoxy, C₁₋₆alkyl, or        trifluoromethyl;    -   1.25 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.24,        wherein R¹ is phenyl;    -   1.26 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.25,        wherein R¹ is p-methoxyphenyl, m-trifluoromethylphenyl or        p-methylphenyl;    -   1.27 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.22,        wherein R¹ is hetaryl optionally substituted except at the ortho        position of the hetaryl with 1-6 halo, C₁₋₆alkoxy, C₁₋₆alkyl, or        trifluoromethyl substituents;    -   1.28 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.22        or 1.27, wherein R¹ is pyridyl;    -   1.29 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.22        or 1.27-1.28, wherein R¹ is pyrid-3-yl;    -   1.30 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.29,        wherein R² is C₀₋₆alkyl, C₃₋₇cycloalkyl, aryl, hetaryl,        aryl(C₁₋₄alkyl)-, hetcyclyl(C₀₋₄alkyl)-, or        —C₀₋₆alkyl-N(C₀₋₆alkyl)(C₀₋₆alkyl), optionally substituted with        C₁₋₆alkyl;    -   1.31 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.30,        wherein R² is hetcyclyl(C₀₋₄alkyl)- optionally substituted with        C₁₋₆alkyl;    -   1.32 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.31,        wherein R² is piperidin-1-yl(C₀₋₄alkyl)-,        piperidin-4-yl(C₀₋₄alkyl)-, piperazin-1-yl(C₀₋₄alkyl) or        piperazin-4-yl(C₀₋₄alkyl), optionally substituted with        C₁₋₆alkyl;    -   1.33 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.32,        wherein R² is piperidin-1-ylmethyl-,        4-methylpiperidin-1-ylmethyl, N-methylpiperidin-4-ylmethyl-,        piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl or        4-ethylpiperazin-1-ylmethyl;    -   1.34 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.33,        wherein R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are independently selected        from hydrogen, halo, C₁₋₄alkyl (e.g., methyl), C₁₋₄alkoxyl        (e.g., methoxy), and haloC₁₋₄alkyl (e.g., trifluoromethyl);    -   1.35 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.34,        wherein R³ is hydrogen;    -   1.36 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.35,        wherein R⁴ is hydrogen;    -   1.37 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.36,        wherein R⁴ is C₁₋₄alkyl (e.g., methyl);    -   1.38 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.35        or 1.37, wherein R⁴ is methyl;    -   1.39 Compounds of Formula (Q) or Formula (I) or any of 1.1-1.38,        wherein, the present invention comprises any of the following        compounds:

in free or salt form.

The term “alkyl” includes both straight and branched chain alkyl groups.References to individual alkyl groups such as “propyl” are specific forthe straight chain version only and references to individual branchedchain alkyl groups such as ‘isopropyl’ are specific for the branchedchain version only. For example, “C₁₋₆alkyl” includes C₁₋₄alkyl,C₁₋₃alkyl, propyl, isopropyl and t-butyl. A similar convention appliesto other radicals, for example “phenylC₁₋₆alkyl” includesphenylC₁₋₄alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. “C₀alkyl”refers to a hydrogen terminus when the C₀alkyl is terminal and refers toa direct bond when the “C₀alkyl” is bridging (linking). The term“C₀₋₆alkyl”, for example, refers to adding “C₀alkyl” to the scope of the“C₁₋₆alkyl” definition. Thus, it is understood that substituents allowedfor “C₁₋₆alkyl” would accordingly be allowed for the “C₁₋₆alkyl” withinthe scope of “C₀₋₆alkyl”.

The term “halo” refers to fluoro, chloro, bromo and iodo.

Where optional substituents are chosen from, for example, “1-5independent” substituents from a list of substituents, it is to beunderstood that this definition includes all substituents being chosenfrom one of the specified groups or the substituents being chosen fromtwo or more of the specified groups in the list. Where a substituent isrecited using the molecule (parent) name, it is understood that thesubstituent is the radical of such molecular parent.

An “aryl” is well understood by one in the art and includes phenyl andnaphthyl.

A “hetaryl” is a 4-12 membered fully unsaturated or partiallyunsaturated heterocyclic mono or bicyclic ring containing at least onenitrogen, sulphur or oxygen ring atom and in which, unless otherwisespecified, a —CH₂— group can optionally be replaced by a —C(O)—.Examples of such hetaryl include indolyl, pyridyl, furyl, thienyl,pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, isobenzofuranyl,2,3-dihydrobenzofuranyl, imidazo[1,2-a]pyridinyl, benzimidazolylquinolyl, pyrrolinyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl,isoxazolyl, benzoxazolyl, benzoxazol-2-one, benzopyridazin-dione,pyridine-N-oxide, and quinoline-N-oxide.

A “hetcyclyl” is a saturated, mono or bicyclic ring containing 4-12atoms containing at least one nitrogen, sulphur or oxygen ring atom.Examples of such “hetcyclyl” include pyrrolidinyl, imidazolidinyl,pyrazolininyl, tetrahydropyranyl, morpholino, piperidyl, andpiperazinyl.

Examples of “C₁₋₆alkoxy” include methoxy, ethoxy and propoxy.

Examples of “—(C₀₋₆alkyl)-N(C₀₋₆alkyl)(C₀₋₆alkyl)” include methylamino,ethylamino, di-N-methylamino, di-(N-ethyl)amino, andN-ethyl-N-methylamino.

A suitable salt of a compound of the invention is, for example, anacid-addition salt of a compound of the invention which is sufficientlybasic, for example, an acid-addition salt with, for example, aninorganic or organic acid, for example hydrochloric, hydrobromic,sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. Inaddition a suitable salt of a compound of the invention which issufficiently acidic is an alkali metal salt, for example a sodium orpotassium salt, an alkaline earth metal salt, for example a calcium ormagnesium salt, an ammonium salt or a salt with an organic base whichaffords a physiologically-acceptable cation, for example a salt withmethylamine, dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine. The Compounds of the Invention, e.g.,compounds of formula (Q) or formula (I), e.g., any of 1.1-1.39, areintended for use as pharmaceuticals, therefore pharmaceuticallyacceptable salts are preferred. Salts which are unsuitable forpharmaceutical uses may nevertheless be useful, for example, for theisolation or purification of free Compounds of the Invention.Consequently, the present invention encompasses novel Compounds ofFormula (Q) and formula (I), in free or salt form, including salts thatare suitable as well as salts which are unsuitable for pharmaceuticaluse.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the formula(I), or a pharmaceutically acceptable salt thereof, as definedhereinbefore, in association with a pharmaceutically-acceptable diluentor carrier. In another aspect of the invention, there is provided apharmaceutical composition which comprises a compound of formula (Q) orformula (I), e.g., any of 1.1-1.39, in free or pharmaceuticallyacceptable salt form, in association with a pharmaceutically acceptablediluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 1-1000 mg/kg, andthis normally provides a therapeutically-effective dose. Preferably adaily dose in the range of 10-100 mg/kg is employed. Similarly, thecompound of formula (Q) or any of 1.1-1.39 may also be administered to awarm-blooded animal at a unit dose within the range of 1-1000 mg/kg,preferably a daily dose in the range of 10-100 mg/kg. However the dailydose will necessarily be varied depending upon the host treated, theparticular route of administration, and the severity of the illnessbeing treated. Accordingly the optimum dosage may be determined by thepractitioner who is treating any particular patient.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined hereinbefore for use in a method of treatment of thehuman or animal body by therapy. The invention also provides a compoundof formula (Q), or any of 1.1-1.39, in free or pharmaceuticallyacceptable salt form, for use in a method of treatment of the human oranimal body by therapy.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt thereof, can penetrate the blood-brainbarrier and inhibit the formation and accumulation of beta-amyloid.Accordingly the compounds of the present invention are useful in thetreatment of neurodegenerative diseases, particularly Alzheimer'sdisease. Therefore, the invention provides a compound of formula (Q) orformula (I), e.g., any of 1.1-1.39, in free or pharmaceuticallyacceptable salt form, which penetrates the blood-brain barrier andinhibit the formation and accumulation of beta-amyloid. The inventionalso provides a compound of formula (Q) or formula (I), e.g., any of1.1-1.39, in free or pharmaceutically acceptable salt form, useful forthe treatment of neurodegenerative diseases, particularly Alzheimer'sdisease.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt thereof, can inhibit certain kinases.Accordingly the compounds of the present invention are useful in thetreatment of cancers of the central nervous system. Therefore, theinvention provides a compound of formula (q) or formula (I), e.g., anyof 1.1-1.39, in free or pharmaceutically acceptable salt form, useful inthe treatment of cancers of the central nervous system.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined hereinbefore for use as a medicament.

According to a further aspect of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined hereinbefore in the manufacture of a medicament foruse in the inhibition of the formation and accumulation of beta-amyloidin a warm-blooded animal such as man. Use of a compound of the formula(Q) or formula (I), e.g., any of 1.1-1.39, in free or pharmaceuticallyacceptable salt form, as defined hereinbefore in the manufacture of amedicament for use in the inhibition of the formation and accumulationof beta-amyloid in a warm-blooded animal such as man.

According to an aspect of the invention there is provided the use of acompound of the formula (I), or a pharmaceutically acceptable saltthereof, as defined hereinbefore in the manufacture of a medicament foruse in the production of an inhibition of certain kinases across theblood-brain barrier in a warm-blooded animal such as man. In anotheraspect, the invention also provides use of a compound for formula (Q) orformula (I), e.g., any of 1.1-1.39, in free or pharmaceuticallyacceptable salt form, in the manufacture of a medicament for use in theproduction of an inhibition of certain kinases across the blood-brainbarrier in a warm-blooded animal such as a man.

According to a further feature of the invention, there is provided theuse of a compound of the formula (I), in free or salt form, as definedherein before in the manufacture of a medicament for use in thetreatment of cancers of the nervous system and the brain. In stillanother feature of the invention, there is provided use of a compound ofthe formula (Q) or formula (I), e.g., any of 1.1-1.39, in free orpharmaceutically acceptable salt form, as defined herein before in themanufacture of a medicament for use in the treatment of cancers of thenervous system and the brain.

According to a further feature of this aspect of the invention there isprovided a method for producing an inhibitory effect against theaccumulation of abnormal protein aggregates in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof. In still another feature ofthis aspect of the invention, there is provided a method for producingan inhibitory effect against the accumulation of abnormal proteinaggregates in a warm-blooded animal, such as man, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of formula (Q) or formula (I), e.g., any of1.1-1.39, in free or pharmaceutically acceptable salt form.

Furthermore, the compounds of this invention are useful in thetreatment, control and management of diseases characterized byaccumulation of abnormal protein aggregates, especially in the brain—forexample, diseases such as Alzheimer's disease, progressive supranuclearpalsy, Down Syndrome, memory and cognitive disorders, dementia, amyloidneuropathies, brain inflammation, nerve and brain trauma, vascularamyloidosis, cerebral hemorrhage with amyloidosis, Parkinson's disease,Huntington's disease, prion disease and/or vascular, neurological,and/or neurodegenerative disorders related to the abnormal expression oraccumulation of tau or amyloid proteins such as Aβ. Such abnormalprotein aggregates include, for example, i) amyloid plaques andneurofibrillary tangles, and ii) precipitates of tau or amyloid proteinssuch as Aβ.

Accordingly, the present invention provides methods of treatment ofAlzheimer's disease, progressive supranuclear palsy, Down Syndrome,memory and cognitive disorders, dementia, amyloid neuropathies, braininflammation, nerve and brain trauma, vascular amyloidosis, cerebralhemorrhage with amyloeiosis, Parkinson's disease, Huntington's disease,prion disease and/or vascular, neurological, and/or neurodegenerativedisorders related to the abnormal expression or accumulation of tau oramyloid proteins such as Aβ. Therefore, the invention provides a methodfor the treatment of Alzheimer's disease, progressive supranuclearpalsy, Down Syndrome, memory and cognitive disorders, dementia, amyloidneuropathies, brain inflammation, nerve and brain trauma, vascularamyloidosis, cerebral hemorrhage with amyloeiosis, Parkinson's disease,Huntington's disease, prion disease and/or vascular, neurological,and/or neurodegenerative disorders related to the abnormal expression oraccumulation of tau or amyloid proteins such as Aβ, which methodcomprises administering to a patient in need thereof, a compound offormula (Q) or formula (I), e.g., any of 1.1-1.39, in free orpharmaceutically acceptable salt form.

Additionally, the present invention provides methods of treatment ofhyperproliferative diseases, especially cancers of the brain or centralnervous system, including astrocytoma, medulloblastoma,oligdendroglioma, glioblastoma, glioma, ependymoma, meningioma, sarcoma,germ cell tumor, pinealoma, craniopharyngioma, and pituitary adenoma.The present invention also provides methods of treatment ofhyperproliferative diseases as described herein comprising administeringto a patient in need thereof a compound of formula (Q) or formula (I),e.g., any of 1.1-1.39, in free or pharmaceutically acceptable salt form.

The present invention also provides methods of treatment of diseasecharacterized by dysfunctional expression or activity of kinases such asthe c-Ab1, BCR-Ab1, ARG, c-Src, c-Kit, FAK, Trk, EGFR, VEGFR, Tie-2,c-Met, FGFR-1, Flt-1, Her-2, c-Raf, PDGFR, PDGFR-beta, MAPK, PKA, PKC,PKCα, PKCδ, CDK5, GSK-3, or JNK, especially over-expression orover-activity of kinases in CNS cells, comprising the administration ofan effective amount of a compound or composition of the presentinvention in free or salt form to a human or animal patient in needthereof. The compound or composition of the present invention includescompounds of formula (Q) or formula (I), e.g., any of 1.1-1.39, in freeor pharmaceutically acceptable salt form.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined herein before inassociation with a pharmaceutically-acceptable diluent or carrier foruse in the treatment, control and management of diseases characterizedby accumulation of abnormal protein aggregates, especially in the brain,such as Alzheimer's disease, progressive supranuclear palsy, DownSyndrome, memory and cognitive disorders, dementia, amyloidneuropathies, brain inflammation, nerve and brain trauma, vascularamyloidosis, cerebral hemorrhage with amyloidosis, Parkinson's disease,Huntington's disease, prion disease and/or vascular, neurological,and/or neurodegenerative disorders related to the abnormal expression oraccumulation of tau or amyloid proteins such as Aβ. In anotherembodiment, the invention provides a pharmaceutical composition whichcomprises a compound of the formula (Q) or formula (I), e.g., any of1.1-1.39, in free or pharmaceutically acceptable salt form, as definedherein before in association with a pharmaceutically-acceptable diluentor carrier for use in the treatment, control and management of diseasescharacterized by accumulation of abnormal protein aggregates, especiallyin the brain, such as Alzheimer's disease, progressive supranuclearpalsy, Down Syndrome, memory and cognitive disorders, dementia, amyloidneuropathies, brain inflammation, nerve and brain trauma, vascularamyloidosis, cerebral hemorrhage with amyloidosis, Parkinson's disease,Huntington's disease, prion disease and/or vascular, neurological,and/or neurodegenerative disorders related to the abnormal expression oraccumulation of tau or amyloid proteins such as Aβ. Such abnormalprotein aggregates include, for example, i) amyloid plaques andneurofibrillary tangles, and ii) precipitates of tau or amyloid proteinssuch as Aβ.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined herein before inassociation with a pharmaceutically-acceptable diluent or carrier foruse in the treatment of Alzheimer's disease, progressive supranuclearpalsy, Down Syndrome, memory and cognitive disorders, dementia, amyloidneuropathies, brain inflammation, nerve and brain trauma, vascularamyloidosis, cerebral hemorrhage with amyloeiosis, Parkinson's disease,Huntington's disease, prion disease and/or vascular, neurological,and/or neurodegenerative disorders related to the abnormal expression oraccumulation of tau or amyloid proteins such as Aβ. In still anotheraspect of the invention, there is provided a pharmaceutical compositionwhich comprises a compound of the formula (Q) or formula (I), any of1.1-1.39, in free or pharmaceutically acceptable salt form, as definedherein before in association with a pharmaceutically acceptable diluentor carrier for use in the treatment of Alzheimer's disease, progressivesupranuclear palsy, Down Syndrome, memory and cognitive disorders,dementia, amyloid neuropathies, brain inflammation, nerve and braintrauma, vascular amyloidosis, cerebral hemorrhage with amyloeiosis,Parkinson's disease, Huntington's disease, prion disease and/orvascular, neurological, and/or neurodegenerative disorders related tothe abnormal expression or accumulation of tau or amyloid proteins suchas Aβ.

The treatment methods include administering the compounds of the presentinvention, e.g., a compound of formula (Q) or formula (I), e.g., any of1.1-1.39, in free or salt form, together with other therapeuticcompounds to treat Alzheimer's disease, progressive supranuclear palsy,Down Syndrome, memory and cognitive disorders, dementia, amyloidneuropathies, brain inflammation, nerve and brain trauma, vascularamyloidosis, cerebral hemorrhage with amyloeiosis, Parkinson's disease,Huntington's disease, prion disease and/or vascular, neurological,and/or neurodegenerative disorders related to the abnormal expression oraccumulation of tau or amyloid proteins such as Aβ.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofinhibitors of accumulation of abnormal protein aggregates, especially inthe brain, as part of the search for new therapeutic agents.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined herein before inassociation with a pharmaceutically-acceptable diluent or carrier foruse in the of treatment of hyperproliferative diseases, especiallycancers of the brain or central nervous system, including astrocytoma,medulloblastoma, oligdendroglioma, glioblastoma, glioma, ependymoma,meningioma, sarcoma, germ cell tumor, pinealoma, craniopharyngioma, andpituitary adenoma. In another aspect, the invention also provides apharmaceutical composition which comprises a compound of formula (Q) or(I), e.g., any of 1.1-1.39, in free or pharmaceutically acceptable saltthereof, as defined herein before in association with apharmaceutically-acceptable diluent or carrier for use in the oftreatment of hyperproliferative diseases, especially cancers of thebrain or central nervous system, including astrocytoma, medulloblastoma,oligdendroglioma, glioblastoma, glioma, ependymoma, meningioma, sarcoma,germ cell tumor, pinealoma, craniopharyngioma, and pituitary adenoma.

In a further aspect of the invention there is provided a pharmaceuticalcomposition which comprises a compound of the formula (I), or apharmaceutically acceptable salt thereof, as defined herein before inassociation with a pharmaceutically-acceptable diluent or carrier foruse in the treatment of astrocytoma, medulloblastoma, oligdendroglioma,glioblastoma, glioma, ependymoma, meningioma, sarcoma, germ cell tumor,pinealoma, craniopharyngioma, and pituitary adenoma. In still anotheraspect, the invention provides a compound of the formula (Q) or formula(I), e.g., any of 1.1-1.39, in free or pharmaceutically acceptable saltform, as defined herein before in association with apharmaceutically-acceptable diluent or carrier for use in the treatmentof astrocytoma, medulloblastoma, oligdendroglioma, glioblastoma, glioma,ependymoma, meningioma, sarcoma, germ cell tumor, pinealoma,craniopharyngioma, and pituitary adenoma.

The treatment methods include administering the compounds of the presentinvention, e.g., compound of formula (Q) or formula (I), e.g., any of1.1-1.39, in free or salt form, together with other therapeuticcompounds to treat hyperproliferative diseases, especially cancers ofthe brain or central nervous system, including astrocytoma,medulloblastoma, oligdendroglioma, glioblastoma, glioma, ependymoma,meningioma, sarcoma, germ cell tumor, pinealoma, craniopharyngioma, andpituitary adenoma.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

In addition to their use in therapeutic medicine, the compounds offormula (I) and their pharmaceutically acceptable salts are also usefulas pharmacological tools in the development and standardisation of invitro and in vivo test systems for the evaluation of the effects ofdysfunctional expression or activity of kinases such as the c-Ab1,BCR-Ab1, ARG, c-Src, c-Kit, FAK, Trk, EGFR, VEGFR, Tie-2, c-Met, FGFR-1,Flt-1, Her-2, c-Raf, PDGFR, PDGFR-beta, MAPK, PKA, PKC, PKCα, PKCδ,CDK5, GSK-3, or JNK, especially over-expression or over-activity ofkinases in CNS cells, as part of the search for new therapeutic agents.Similarly, the compounds of formula (Q), e.g., any of 1.1-1.39, in freeor pharmaceutically acceptable salt forms, are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects ofdysfunctional expression or activity of kinases as hereinbeforedescribed.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated by the following non limitingexamples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature (“rt”) were at a temperaturein the range of 18-25° C.;

(ii) organic solutions were dried over anhydrous sodium sulphate;evaporation of solvent is carried out using a rotary evaporator underreduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperatureof up to 60° C.;

(iii) in general, the course of reactions is followed by TLC andreaction times are given for illustration only;

(iv) final products had satisfactory proton nuclear magnetic resonance(NMR) spectra and/or mass spectral data;

(v) yields are given for illustration only and are not necessarily thosewhich can be obtained by diligent process development; preparations wererepeated if more material is required;

(vii) when given, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 400 MHzusing perdeuterio dimethyl sulphoxide (DMSO-d₆) as solvent unlessotherwise indicated;(vii) chemical symbols have their usual meanings; SI units and symbolsare used;(viii) solvent ratios are given in volume:volume (v/v) terms; and(ix) mass spectra were run with an electron energy of 70 electron voltsin the chemical ionization (CI) mode using a direct exposure probe;where indicated ionization is effected by electron impact (EI), fastatom bombardment (FAB) or electrospray (ESP); values for m/z are given;generally, only ions which indicate the parent mass are reported; andunless otherwise stated, the mass ion quoted is [MH]⁺;(x) where a synthesis is described as being analogous to that describedin a previous example the amounts used are the millimolar ratioequivalents to those used in the previous example;(xi) the following abbreviations have been used:

Cs₂CO₃ cesium carbonate; HOBt 1H-benzo[d][1,2,3]triazol-1-ol; HPLC highperformance liquid chromatography; MeOH methanol; NaHCO₃ sodiumbicarbonate; BOP benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate; THF tetrahydrofuran; DMF N,N-dimethylformamide;EtOAc ethyl acetate; DIEA N,N-diisopropylethylamine; DCMdichloromethane; DMSO dimethylsulphoxide; and MeCN acetonitrile;(xii) “ISCO” refers to normal phase flash column chromatography using 12g and 40 g pre-packed silica gel cartridges used according to themanufacturer's instructions obtained from ISCO, Inc, 4700 superiorstreet Lincoln, Nebr., U.S.A.

Example 14-((4-ethylpiperazin-1-yl)methyl)-N-(6-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-ylamino)pyridin-3-yl)benzamide

(a)(2-Methyl-5-nitro-pyridin-3-yl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine

To a mixture of 3-bromo-2-methyl-5-nitro-pyridine (380 mg, 1.75 mmol)and 4-pyridin-3-yl-pyrimidin-2-ylamine (250 mg, 1.45 mmol) in drytoluene (20 mL) were added Cs₂CO₃ (710 mg, 2.18 mmol), Pd₂(dba)₃ (26 mg,0.028 mmol) and Xantphos (50 mg, 0.086 mmol). The mixture was evacuatedand purged with N₂ (3 cycles), heated to 90° C. under N₂ for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was cooled to rt,diluted with EtOAc and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by column chromatography(SiO₂) using CH₂Cl₂-MeOH (98:2) to afford product (225 mg, 50%). ¹H NMR(200 MHz, CDCl₃): δ 2.76 (s, 3H), 7.23 (m, 1H), 7.38 (d, J=6.0 Hz, 1H),7.51 (m, 1H), 8.51 (m, 1H), 8.63 (d, J=6.0 Hz, 1H), 8.77 (m, 1H), 9.04(d, J=2.0 Hz, 1H), 9.28 (d, J=2.0 Hz, 1H), 9.77 (d, J=2.0 Hz, 1H); Mass[M+H]⁺: 309.

(b) 2-Methyl-N³-(4-pyridin-3-yl-pyrimidin-2-yl)-pyridine-3,5-diamine

A mixture of(2-methyl-5-nitro-pyridin-3-yl)-(4-pyridin-3-yl-pyrimidin-2-yl)-amine(450 mg, 11.84 mmol), catalytic ferric chloride (50 mg) in hydrazinehydrate (20 mL) and methanol (20 mL) was refluxed for 1 h. The reactionmixture was cooled to rt, concentrated under reduced pressure and thecrude residue was diluted with water (10 mL) and extracted with EtOAc(2×25 mL). The combined extracts were dried over anhydrous Na₂SO₄,filtered, concentrated under reduced pressure. The residue was stirredwith hexane (20 mL) for 5 min, the hexane layer was decanted and theresidue was dried to give 280 mg of product as a pale yellow solid(Yield: 68%). Mp: 135° C.; ¹H NMR (200 MHz, CDCl₃): δ 2.51 (s, 3H), 3.65(bs, 2H), 6.99 (s, 1H), 7.22 (d, J=4.0 Hz, 1H), 7.44 (m, 1H), 7.78 (d,J=10.0 Hz, 1H), 8.05 (d, J=2 Hz, 1H), 8.36-8.31 (m, 1H), 8.51 (d, J=4.0Hz, 1H), 8.75-8.72 (m, 1H), 9.27 (d, J=2.0 Hz, 1H); Mass [M+H]⁺: 279.

(c)4-((4-ethylpiperazin-1-yl)methyl)-N-(6-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-ylamino)pyridin-3-yl)benzamide

DIEA (47 μL, 0.27 mmol) was added into a solution of2-Methyl-N³-(4-pyridin-3-yl-pyrimidin-2-yl)-pyridine-3,5-diamine (15 mg,0.054 mmol), 4-((4-ethylpiperazin-1-yl)methyl)benzoic acid (16.1 mg,0.61 mmol), BOP (33.4 mg, 0.76 mmol) in DMF (1.5 mL). The reactionmixture is stirred at rt under argon atmosphere overnight. The reactionmixture was then purified by Waters semi-preparative HPLC to the finalproduct. MS (ESI⁺) m/z 509.1 [M+H]⁺.

Example 24-((4-ethylpiperazin-1-yl)methyl)-N-(6-methyl-5-(4-phenylpyrimidin-2-ylamino)pyridin-3-yl)benzamide

The synthesis method is analogous to EXAMPLE 1 wherein4-phenylpyrimidin-2-amine was added in step (a) instead of4-pyridin-3-yl-pyrimidin-2-ylamine (overall yield: 33.7%). MS (ESI⁺) m/z508.1 [M+H]⁺.

Example 3N-(6-methyl-5-(4-phenylpyrimidin-2-ylamino)pyridin-3-yl)-4-((1-methylpiperidin-4-yl)methyl)benzamide

The synthesis method is analogous to EXAMPLE 1 wherein4-phenylpyrimidin-2-amine was added in step (a) instead of4-pyridin-3-yl-pyrimidin-2-ylamine, and4-((1-methylpiperidin-4-yl)methyl)benzoic acid was used in step (c)instead of 4-((4-ethylpiperazin-1-yl)methyl)benzoic acid (overall yield:10.2%). MS (ESI⁺) m/z 493.1 [M+H]⁺.

Example 4N-(6-methyl-5-(4-(pyridin-3-yl)pyrimidin-2-ylamino)pyridin-3-yl)picolinamide

Picolinoyl chloride hydrochloride salt (96 mg, 0.54 mmol) was added intoa solution of2-methyl-N³-(4-pyridin-3-yl-pyrimidin-2-yl)-pyridine-3,5-diamine (50 mg,0.18 mmol) in pyridine (1.5 mL). The reaction mixture was stirred at rtunder argon atmosphere overnight. After pyridine is removed underreduced pressure, the residue is purified by chromatography to give 10.4mg of the product as pale yellow solids (Yield: 15%). MS (ESI⁺) m/z384.3 [M+H]⁺

Example 5N-(6-methyl-5-(4-phenylpyrimidin-2-ylamino)pyridin-3-yl)picolinamide

Picolinoyl chloride hydrochloride salt (64 mg, 0.36 mmol) was added intoa solution of 2-methyl-N-3-(4-phenylpyrimidin-2-yl)pyridine-3,5-diamine(50 mg, 0.18 mmol) in pyridine (2.5 mL). The reaction mixture wasstirred at rt under argon atmosphere for about 60 h. After pyridine isremoved under reduced pressure, the residue is purified bychromatography to give 9.1 mg of the product as pale yellow solids(Yield: 13%). MS (ESI⁺) m/z 383.2 [M+H]⁺

Example 6N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-5-(4-phenylpyrimidin-2-ylamino)nicotinamide

(a) 5-bromo-N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide

DIEA (473 μL, 2.72 mmol) was added into a solution of 5-bromonicotinicacid (178 mg, 0.881 mmol), 4-((4-methylpiperidin-1-yl)methyl)benzenamine(150 mg, 0.734 mmol), BOP (487 mg, 1.10 mmol) in DMF (3 mL). Thereaction mixture is stirred at rt under argon atmosphere overnight. Thereaction mixture was diluted with 80 mL of AcOEt, and then washed with1N NaOH aqueous solution three times. Organic phase was dried withanhydrous Na₂SO₄, and then evaporated to remove organic solvents. Theobtained residue was further dried under high vacuum overnight to givecrude product, which was used directly for the next step synthesiswithout further purification. MS (ESI⁺) m/z 388.1 [M+H]⁺.

(b)N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-5-(4-phenylpyrimidin-2-ylamino)nicotinamide

A mixture of5-bromo-N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide (45.6mg, 0.1 mmol) and 4-phenylpyrimidin-2-amine (25.7 mg, 0.15 mmol),KOBu^(t) (22.4 mg, 0.2 mmol), Pd₂(dba)₃ (4.6 mg, 0.005 mmol) andXantphos (4.6 mg, 0.008 mmol) in a microwave reaction vessel wassuspended in 2 mL of THF. The reaction mixture was heated in a microwaveat 150° C. for 90 min. After cooling, the mixture was diluted with DMF,and then filtered with a 0.45 μm microfilter. The obtained filtrate wasseparated by a semi-preparative HPLC. Collected product fraction waslyophilized to give pure product as a while powder (20 mg, 38%). MS(ESI⁺) m/z 479.2 [M+H]⁺.

Example 7N-(6-methyl-5-(4-phenylpyrimidin-2-ylamino)pyridin-3-yl)-4-((1-methylpiperidin-4-yl)methyl)benzamide

The synthesis method is analogous to EXAMPLE 1 wherein4-phenylpyrimidin-2-amine was added in step (a) instead of4-pyridin-3-yl-pyrimidin-2-ylamine, and4-(piperidin-1-ylmethyl)-3-(trifluoromethyl)benzoic acid was used instep (c) instead of 4-((4-ethylpiperazin-1-yl)methyl)benzoic acid. MS(ESI⁺) m/z 547.1 [M+H]⁺.

Example 85-(5-methyl-4-phenylpyrimidin-2-ylamino)-N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide

The synthesis method is analogous to EXAMPLE 6 wherein5-methyl-4-phenylpyrimidin-2-amine was added in step (b) instead of4-phenylpyrimidin-2-amine. MS (ESI⁺) m/z 493.2 [M+H]⁺.

Example 9N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-5-(4-(3-(trifluoromethyl)phenyl)pyrimidin-2-ylamino)nicotinamide

The synthesis method is analogous to EXAMPLE 6 wherein4-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine was added in step (b)instead of 4-phenylpyrimidin-2-amine. MS (ESI⁺) m/z 547.2 [M+H]⁺.

Example 10N-(4-((4-Methylpiperidin-1-yl)methyl)phenyl)-2-(4-(3-(trifluoromethyl)phenyl)pyrimidin-2-ylamino)isonicotinamide

The synthesis method is analogous to EXAMPLE 6 wherein2-bromoisonicotinic acid was added in step (a) instead of5-bromonicotinic acid, and4-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine was added in step (b)instead of 4-phenylpyrimidin-2-amine. MS (ESI⁺) m/z 547.2 [M+H]⁺.

Example 11 N2a Cell Assay

Evaluation of Amyloid Beta (Aβ) Production in N2a Cells.

The influence of compounds on Aβ production in N2a cells is carried outas described by Netzer, W. J., Dou, F., Cai, D., Veach, D., Jean, S.,Li, Y., Bornmann, W. G., Clarkson, B., Xu, H., and Greengard, P. (2003)Proc Natl Acad Sci USA 100, 12444-12449. The exemplified Compounds ofthe Invention inhibit amyloid beta by at least 50% at concentrations 10micromolar over 24 hours.

Example 12 Mouse Brain/Plasma Distribution Assay for the Evaluation ofTissue Levels of Test Compounds

Compounds are administered sub-cutaneously to C57bl/6 black mice as asingle injection of 1 mg using a 10 mM DMSO solution. After 2 or 4hours, the mice are sacrificed. Trunk blood is collected into tubes withpotassium-EDTA as anticoagulant and centrifuged at 5000×g for 10 min.The upper plasma phase is decanted from cellular components. Whole brainis sonicated with 20 mM Tris-HCl, 135 mM NaCl, pH 7.4 buffer, giving at200 mg/mL (w/v) homogenate. Brain homogenate or plasma is extracted with2 volumes of acetonitrile and clarified by centrifugation at 15,000×gfor 20 min. Extracts are separated by HPLC using a Waters Alliance 2695separations module with a Sunfire™ C18 column (3.5 micron, 2.1×50 mm)and a gradient of methanol over 15 min in a mobile phase of 0.1% formicacid. The separation is monitored by a Micromass Quattro Microtriple-quadrupole mass-spectrometric detector. Compound standardizationis performed by methods analogous to those previously reported, e.g., byZhao, M., et al. (2005) J Chromatogr B Analyt Technol Biomed Life Sci819, 73-80; and Appels, N. M et al. (2005) Rapid Commun Mass Spectrom19, 2187-2192.Brain concentration=measured−2% of plasmaB/P ratio=brain concentration/plasma concentration

Exemplified Compounds of the Invention have a B/P ratio in this assay atfour hours post-administration of greater than 0.6, while having a brainconcentration of greater than 0.3 μM at four hours post administrationcompared to the brain concentration of imatinib at four hourspost-administration of less than 0.1 μM, demonstrating a substantiallyhigher level of penetration and accumulation in the brain for theCompounds of the Invention.

What is claimed:
 1. A compound of formula (Q):

in free or salt form, wherein: A¹ is —C(R⁷)— or —N—; A² and A³ areindependently —C— or —N—, wherein at least one of A² and A³ must be N;and wherein when A² or A³ is —C—, it is optionally substituted with R⁸;W is —O— or —N(C₀₋₆alkyl)-; Y is —NHCO—, —CONH—; D is a 5 or 6 memberedaryl, hetaryl or hetcyclic ring having at least one N, S, or O ringatom, or a C ring atom forming an oxo (C═O) moiety; R¹ is phenyl;optionally substituted except at the ortho position of the phenyl with1-6 halo, C₁₋₆alkoxy, C₁₋₆alkyl, or trifluoromethyl substituents;wherein the ortho phenyl position is unsubstituted; R² ishetcyclyl(C₀₋₄alkyl)-, optionally substituted with C₁₋₆alkyl; and R³,R⁴, R⁵, R⁶, R⁷ and R⁸ are independently selected from hydrogen, halo,C₁₋₄alkyl, C₁₋₄alkoxyl, and haloC₁₋₄alkyl.
 2. The compound according toclaim 1 wherein the compound of formula (Q) is

in free or salt form.
 3. The compound according to claim 1 wherein thecompound of formula (Q) is

in free or salt form.
 4. The compound according to claim 1 wherein thecompound of formula (Q) is

in free or salt form.
 5. The compound according to claim 1 wherein thecompound of formula (Q) is:

in free or salt form.
 6. The compound according to claim 1 wherein thecompound of formula (Q) is:

in free or salt form.
 7. The compound according to claim 1 wherein thecompound of formula (Q) is:

in free or salt form.
 8. A compound of formula (I):

in free or salt form, wherein: A¹ is CH or N; A² and A³ areindependently CH or N, wherein at least one of A² and A³ must be N; andwherein when A² or A³ is C, it is optionally substituted with halo,methyl, methoxy, or trifluoromethyl; W is —O— or —N(C₀₋₆alkyl)-; Y is—NHCO—, —CONH—, —NHSO₂—, —NHCONH—, or —NHCH₂—; D is a 5 or 6 memberedaryl, hetaryl or hetcyclic ring having at least one N, S, or O ringatom, or a C ring atom forming an oxo (C═O) moiety; R¹ is phenyl;optionally substituted except at the ortho position of the phenyl with1-6 halo, C₁₋₆alkoxy, C₁₋₆alkyl, or trifluoromethyl substituents;wherein the ortho phenyl position is unsubstituted; and R² ishetcyclyl(C₀₋₄alkyl)-, optionally substituted with C₁₋₆alkyl.
 9. Apharmaceutical composition which comprises a compound, in free orpharmaceutically acceptable salt form, according to claim 1, inassociation with a pharmaceutically-acceptable diluent or carrier.
 10. Amethod of treatment of a disease or disorder characterized as aneurodegenerative disease comprising administering an effective amountof the compound according to claim 1, in free or pharmaceuticallyacceptable salt form, to a patient in need thereof.
 11. The methodaccording to claim 10, wherein the disease or disorder characterized asa neurodegenerative disease is selected from the group consisting of:Alzheimer's disease, progressive supranuclear palsy, Down Syndrome,dementia, amyloid neuropathies, brain inflammation, nerve and braintrauma, vascular amyloidosis, cerebral hemorrhage with amyloidosis,Parkinson's disease, Huntington's disease, and prion disease.
 12. Themethod according to claim 10, wherein said disease or disorder isAlzheimer's disease.
 13. A method of treatment of a disease or disordercharacterized as hyperproliferative comprising administering thecompound according to claim 1, in free or pharmaceutically acceptablesalt form, to a patient in need thereof.
 14. A method of treatment,control and management of diseases characterized by accumulation ofabnormal protein aggregates comprising administering an effective amountof the compound according to claim 1, in free or pharmaceuticallyacceptable salt form, to a patient in need thereof.
 15. The method ofclaim 14, wherein said disease is characterized by accumulation ofabnormal protein aggregates in the brain.
 16. A method of treatment,control and management of vascular, neurological, or neurodegenerativedisorders related to the abnormal expression or accumulation of tau oramyloid proteins, comprising administering an effective amount of thecompound according to claim 1, in free or pharmaceutically acceptablesalt form, to a patient in need thereof.
 17. The method of claim 14,wherein the disease or disorder characterized by the accumulation ofabnormal protein aggregates is selected from the group consisting of:amyloid plaques, neurofibrillary tangles, or precipitates of tau oramyloid proteins.
 18. A method of treatment of disease or disorderscharacterized as cancers of the brain or central nervous system,comprising administering an effective amount of the compound accordingto claim 1, in a free or pharmaceutically acceptable salt form, to apatient in need thereof.
 19. The method of claim 13, wherein the diseaseor disorder characterized as hyperproliferative is selected from thegroup consisting of: astrocytoma, medulloblastoma, oligdendroglioma,glioblastoma, glioma, ependymoma, meningioma, sarcoma, germ cell tumor,pinealoma, craniopharyngioma, and pituitary adenoma.
 20. A method oftreatment of a disease or disorder characterized by dysfunctional kinaseexpression or kinase activity comprising administering an effectiveamount of the compound according to claim 1, in free or pharmaceuticallyacceptable salt form, to a patient in need thereof.
 21. The method ofclaim 20, wherein the disease or disorder characterized by dysfunctionalkinase expression or kinase activity is selected from the followinggroup of kinases consisting of: c-Ab1, BCR-Ab1, ARG, c-Src, c-Kit, FAK,Trk, EGFR, VEGFR, Tie-2, c-Met, FGFR-1, Flt-1, Her-2, c-Raf, PDGFR,PDGFR-beta, MAPK, PKA, PKC, PKCα, PKCδ, CDK5, GSK-3, and JNK.
 22. Themethod of claim 10, wherein the neurodegenerative disease or disorder isa memory or cognitive disorder.
 23. The method of claim 17, wherein thedisease or disorder is Alzheimer's disease and the abnormal proteinaggregates are amyloid plaques.
 24. The compound according to claim 1,wherein W is —NH—, in free or salt form.
 25. The compound according toclaim 1, wherein A¹ is —N—, in free or salt form.
 26. The compoundaccording to claim 1, wherein A² is —C—optionally substituted withmethyl, in free or salt form.
 27. The compound according to claim 1,wherein A³ is —N—, in free or salt form.
 28. The compound according toclaim 1, wherein Y is —NHCO—, in free or salt form.
 29. The compoundaccording to claim 1, wherein D is aryl, in free or salt form.
 30. Thecompound according to claim 1, wherein D is phenyl, in free or saltform.
 31. The compound according to claim 1, wherein R¹ is phenyloptionally substituted except at the ortho position of the phenyl with1-6 halo, C₁₋₆alkoxy, C₁₋₆alkyl, or triflouromethyl, in free or saltform.
 32. The compound according to claim 1, wherein R¹ is phenyl, infree or salt form.
 33. The compound according to claim 1, wherein R² ispiperidin-1-yl(C₀₋₄alkyl)-, piperidin-4-yl(C₀₋₄alkyl)-,piperazin-1-yl(C₀₋₄alkyl)- or piperazin-4-yl(C₀₋₄alkyl)-, optionallysubstituted with C₁₋₆alkyl, in free or salt form.
 34. The compoundaccording to claim 1, wherein R² is piperidin-1-ylmethyl,4-methylpiperidin-1-ylmethyl, N-methylpiperidin-4-ylmethyl,piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl orethylpiperazin-1-ylmethyl, in free or salt form.
 35. The compoundaccording to claim 8, wherein the compound is a compound of formula (I)

in free or salt form, wherein: A¹ is N; A² and A³ are independently CHor N, wherein at least one of A² and A³ must be N; and wherein when A²or A³ is C, it is optionally substituted with halo, methyl, methoxy, ortrifluoromethyl; W is —N(C₀₋₆alkyl)-; Y is —NHCO—, or —CONH—; D is a 5or 6 membered aryl, hetaryl or hetcyclic ring having at least one N, S,or O ring atom; R¹ is phenyl; R² is hetcyclyl(C₀₋₄alkyl)-, optionallysubstituted with C₁₋₆alkyl.
 36. The compound according to claim 35,wherein A² is —C—, optionally substituted with methyl, in free or saltform.
 37. The compound according to claim 35, wherein A³ is —N—, in freeor salt form.
 38. The compound according to claim 35, wherein W is —NH—,in free or salt form.
 39. The compound according to claim 35, wherein Yis —NHCO—, in free or salt form.
 40. The compound according to claim 35,wherein D is aryl, in free or salt form.
 41. The compound according toclaim 35, wherein D is phenyl, in free or salt form.
 42. The compoundaccording to claim 35, wherein R² is piperidin-1-yl(C₀₋₄alkyl)-,piperidin-4-yl(C₀₋₄alkyl)-, piperazin-1-yl(C₀₋₄alkyl)- orpiperazin-4-yl(C₀₋₄alkyl)-, optionally substituted with C₁₋₆alkyl, infree or salt form.
 43. The compound according to claim 35, wherein R² ispiperidin-1-ylmethyl, 4-methylpiperidin-1-ylmethyl,N-methylpiperidin-4-ylmethyl, piperazin-1-ylmethyl,4-methylpiperazin-1-ylmethyl or ethylpiperazin-1-ylmethyl, in free orsalt form.